Effect Of Idronoxil Combined With Cisplatin On Refractory Immune Responses In Nasopharyngeal Carcinoma.

e15186 Background: Nasopharyngeal carcinoma (NPC) is endemic in Southern China. Although it is both radio-and chemo-sensitive, resistance to these treatments remains a major problem for successful management of NPC. The main characteristic of a cancer cell is its resistance to undergo apoptosis; therefore, reversing this resistance may represent the best approach for the treatment of cancer. Additionally, NPC is well-known to be heavily infiltrated by lymphocytes and constitute a unique but poorly defined tumor microenvironment (TME). We aimed at delineating and defining the contribution of idronoxil (IDX) in restoring sensitivity to apoptosis and potentially modulating the immune microenvironment of NPC. Methods: The IC 50 of cisplatin (Cis) and IDX from 2D and 3D spheroid cultures of four NPC cancer cell lines (C666, C17, and the paired NPC43 EBV-positive and EBV-negative cell lines) were evaluated. The migration and proliferation of cells treated with IDX and/or Cis were investigated by Transwell and XTT, respectively. Cell phenotype and migratory analyses were measured by flow cytometry on Cis/IDX-pretreated NPC cell lines cocultured with HLA-matched PBMC. Results: IDX and Cis inhibited NPC migration and cell proliferation (IC 50 for IDX in 2D and 3D was 2µM; IC 50 for Cis in 2D and 3D: was 0.6µM and 1.4µM, respectively). A dose-dependent induction of apoptosis in NPC cell lines by IDX was observed [early apoptotic cells (Annexin V+/PI- at 1µM); late apoptotic cells (Annexin V+/PI+ at 2µM), and necrotic cells (Annexin V-/PI+, at 4µM) were distinguished]. Intriguingly, IDX increased the migratory potential of PBMC towards tumor cells in both 2D and 3D spheroid cultures. Finally, IDX, but not Cis, facilitated the migration of CD8+ T cells toward tumor cells by 3.5-fold (p < 0.05) as well as promoted the expansion of proliferative CD8+ T cells (increased by ~2.8-fold) with degranulation activities (~1.3-fold and 3-fold increase in surface CD107a and intracellular granzyme B expression, respectively) in the cocultures. Conclusions: IDX was shown to induce apoptosis in NPC cells while inhibiting their migration and proliferation. Moreover, the ability of IDX to modulate T cell populations indicates the drug’s potential to enhance the efficacy of current chemotherapy treatments in NPC by upregulating cellular trafficking to the cancer cell.